Project Summary/Abstract Age-related disorders including diabetes have replaced infectious diseases as the leading cause of death in developed countries. There is an urgent need to identify new molecular targets that could lead to better therapeutic and diagnostic strategies for treatment of these disorders. Numerous studies have demonstrated that a highly predictive metabolic characteristic of insulin resistant and diabetic states is a reproducible and significant reduction in the level of glycine in circulation. These observations raise the intriguing possibility that there may be a causal relationship between aberrant glycine metabolism and the development of diabetes, and that the molecular pathways underling glycine homeostasis represent novel molecular targets for diabetes intervention. Glycine plays a key role in multiple cellular processes that, if dysregulated, could influence metabolic health and diabetes susceptibility. In particular, glycine is a required substrate for the biosynthesis of the cellular antioxidant glutathione. Compromised protection against oxidative stress due to a decline in the level of glutathione occurs during aging and is thought to play a key role in the development of many age-related disorders including type 2 diabetes. Glycine levels are controlled primarily by the hepatic glycine cleavage system (GCS), which degrades glycine. The overall activity of the GCS is elevated in diabetes and our preliminary observations indicate that the gene for the rate-limiting enzyme of the GCS, glycine decarboxylase (GLDC), is over-expressed in diabetic animals. Additional preliminary data demonstrate that GLDC gene transcription is regulated by the transcription factor SREBP1c, which is known to be activated by insulin. Based on these observations, we propose that hyperinsulinemia, as seen in insulin resistant states such as obesity, induces an SREBP-mediated increase in hepatic GLDC gene expression, increased glycine degradation, and ultimately reduced levels of glycine in circulation. We further propose that the increase in hepatic glycine degradation induces a feed-forward cascade of events, including increased oxidative stress, that exacerbates the development of type 2 diabetes and other age-related diseases. The overarching goal of this project is to test this model and determine if there is a causal link between glycine metabolism and diabetes susceptibility. This will be accomplished by characterizing the metabolic effects of experimentally altered hepatic GLDC gene expression in lean and obese mice. These studies represent an initial effort to explore the novel and potentially important possibility that hepatic glycine degradation affects disease susceptibility, which if true, would identify GLDC as a potential target for therapeutic intervention for type 2 diabetes and other age- related diseases.